Published papers

The artificial analogs of aplyronine A (1), a potent cytotoxic and antitumor macrolide, were synthesized and the structure-activity (cytotoxicity and actin depolymerizing activity) studies were performed; the side chain portion in 1 was found to play a key role in both biological activities.

Aurilide (1), a new 26-membered cyclodepsipeptide, has been isolated from the Japanese sea hare Dolabella auricularia. The gross structure of 1 was established by spectroscopic analysis. The absolute stereostructure of 1 was determined by HPLC analysis of amino acid components and isoleucic acid obtained from acidic hydrolysis of 1 and by the enantioselective synthesis of the tris(p-bromobenzoate) 3 derived from the dihydroxy acid moiety.

The enantioselective total synthesis of aplyronine A (1), a potent antitumor substance of marine origin, was achieved by a convergent approach. Three segments 4, 5, and 6, corresponding to the C5-C11, C21-C27, and C28-C34 portions of aplyronine A (1), were prepared using the Evans aldol reaction and the Sharpless epoxidation as key steps. The coupling reaction of 4 with iodide 7 followed by Julia olefination with sulfone 8 gave the C5-C20 segment 9, while the Julia coupling reaction between segments 5 and 6 provided the C21-C34 segment 10. Julia olefination between segments 9 and 10 and the subsequent four-carbon homologation reaction led to seco acid 83, which was converted into aplyronine A (1) by Yamaguchi lactonization followed by the introduction of two amino acids. The use of the [(3,4-dimethoxybenzyl)oxy]methyl group as a protecting group for the hydroxyl at C29 was crucial for this synthesis. The enantioselective synthesis of two natural congeners, aplyronines B (2) and C (3), was also carried out using the intermediates for the synthesis of 1, which determined the absolute stereostructures of 2 and 3 unambiguously. To study the structure-cytotoxicity relationships of aplyronines, artificial analogues of 1 were synthesized and their cytotoxicities were evaluated: the trimethylserine moiety, two hydroxyl groups, and the side chain portion in 1 turned out to be important in the potent cytotoxicity shown by 1. Biological studies with aplyronine A (1) showed that 1 inhibited polymerization of G-actin to F-actin and depolymerized F-actin to G-actin.

Two new polypropionates, auripyrones A (1) and B (2), have been isolated as cytotoxins from the sea hare Dolabella auricularia. The gross structures of 1 and 2 were determined by spectroscopic analysis, and their relative stereochemistry except for the ester moiety of 2 was established on the basis of the NOESY data.

Synthesis of aplyronines B and C, the congeners of aplyronine A, was achieved enantioselectively, which established their stereostructures.

The C21-C34 segment 2 of aplyronine A (1), a potent antitumor substance of marine origin, was synthesized enantioselectively in 25 steps (17% overall yield) from imide 11.

Novel bicyclic triols, attenols A (1) and B (2), were isolated from the Chinese bivaive Pinna attenuata. The absolute stereostructures of 1 and 2 were determined by spectroscopic analysis and the modified Mosher's method. These attenols exhibited moderate cytotoxicity against P388 cells.

Novel macrolides, haterumalides NA (1), NB (2), NC (3), ND (4), and NE (5), were isolated from an Okinawan sponge Ircinia sp. The absolute stereostructure of 1 was determined by spectroscopic analysis and modified Mosher's method. Haterumalide NA (1) showed cytotoxicity against P388 cells and acute toxicity against mice.